The present invention relates generally to a family of benztropine compounds or tropane analogs, pharmaceutical compositions comprising them, and their use to treat various diseases or conditions including mental disorders.
The significant public health and social problems resulting from cocaine abuse have stimulated research efforts directed toward elucidating the central mechanisms by which cocaine exerts its behavioral effects. The data from these studies suggest that the primary mechanism of the behavioral effects of cocaine appears to be related to the inhibition of dopamine uptake (see, Ritz, M. C., et al., Science, 237, 1219-1223 (1987); and Kuhar, M. J., et al., Trends Neurosci., 14, 299-301 (1991)) which results in an elevated concentration of dopamine in the synapse. As a consequence, considerable emphasis has been directed toward the dopamine transporter as a target for research and potential therapeutics for the treatment of cocaine abuse.
There have been several approaches to finding tropane analogs as potential medications for psychostimulant abuse and other mental disorders; see, for example, Singh, S., Chem. Rev., 100, 925-1024 (2000); Newman A. H. and Kulkarni S. S., Med. Res. Rev., 22, 429-464 (2002); Newman, A. H., Med. Chem. Res., 8, 1-11 (1998); Carroll, F. I., J. Med. Chem., 46, 1775-1794 (2003), Agoston et al., J. Med. Chem., 40, 4329-39 (1997); Desai et al., J. Neurosci., 25, 1889-93 (Feb. 23, 2005); Kulkami et al., J. Med. Chem., 47, 3388-98 (2004); Xu et al., J. Med. Chem., 45, 1203-10 (2002); Zou et al., Bioorg. Med. Chem. Lett., 12, 1249-52 (2002); Zou et al., J. Med. Chem., 46, 2908-16 (2003); and U.S. Pat. No. 5,792,775. Although some of the reported analogs have demonstrated some cocaine-like discriminative stimulus effects, there remains a need for tropane or benztropine analogs which have affinity for the dopamine transporter but without a significant behavioral profile of cocaine. The present invention provides such analogs. This and other objects and advantages of the invention, as well as additional inventive features will be apparent from the description of the invention provided herein.